A majority of pancreatic cancer (PC) patients (> 80%) present with an unresectable primary tumor with distant metastasis at the time of diagnosis due to its asymptomatic nature and lack of methods for early detection. While the overall 5-year survival rate of PC is dismal, significantly better outcomes have been reported for early stage smaller tumors. PC is believed to progress through a series of histological changes and recent estimates indicate that these changes require 15-20 years to develop into invasive metastatic disease, hence providing a window of opportunity to intervene. While early diagnosis is an obvious strategy to improve the survival of PC patients, lack of non-invasive biomarkers for risk prediction of precursor lesions or early stage invasive disease impedes our ability to diagnose PC during this ?window. Premalignant cystic lesions of the pancreas offer unique opportunity for early diagnosis. To meet the EDRN stated goal of performing a validation study for early cancer detection and risk assessment likely to yield meaningful results within 5 years, we propose an innovative approach that could lead to the development of a clinically useful biomarker in this time frame. Additionally, we propose to study cystic neoplasms since IPMN and MCN offer a unique opportunity to identify pancreatic premalignant lesions and serve as a target for early detection strategies. The candidate biomarkers studies in our application have been identified and evaluated over the past 5 years in EDRN-funded biomarker developmental laboratories (BDLs). Studies from the laboratories of participating investigators have conclusively established that mucin overexpression is a hallmark of pancreatic cancer and have identified biomarkers (MUC5AC and its 2 glycoforms, MUC4 and a glycoform of endorepellin) that can effectively distinguish a) patients with resectable PC patients from patients with benign pancreatic diseases; b) mucinous and nonmucinous cysts; c) high-grade from moderate- and low-grade mucinous cysts and d). high-risk intestinal type IPMNs and low risk gastric type IPMNs. The overall objective of this CVC proposal is to demonstrate the ability of the aforementioned biomarkers to distinguish pancreatic adenocarcinoma (PC) patients from healthy controls, patients with benign biliary obstruction and chronic pancreatitis (CP), and to identify those cysts with high malignant potential. We have a large number of high quality, well-characterized specimens from patients with pancreatic disease and diseased controls that were collected and processed following protocols developed through the EDRN.
Two specific aims are proposed.
Aim 1 will use available samples from our biospecimen repository to evaluate MUC5AC and MUC4 as biomarkers to distinguish pancreatic adenocarcinoma (PC) patients from healthy controls, and from patients with benign biliary obstruction and chronic pancreatitis (CP).
Aim 2 will determine if our biomarkers can identify those cysts with high lethal potential from those with a low risk for malignant transformation.
The objective of this Clinical Validation Center (CVC) proposal is to validate biomarkers (MUC5AC and MUC4) in blood; cystic fluids and tissues. While early diagnosis of pancreatic cancer (PC) can positively impact prognosis; it remains challenging due to asymptomatic nature; lack of early biomarkers and limited availability of samples. Most importantly we propose to prospectively collect specimens from high risk subjects (pancreatic cystic neoplasms and PC) to evaluate biomarkers for risk diagnosis and prognosis.
| Cannon, Andrew; Thompson, Christopher; Hall, Bradley R et al. (2018) Desmoplasia in pancreatic ductal adenocarcinoma: insight into pathological function and therapeutic potential. Genes Cancer 9:78-86 |
| Nimmakayala, Rama Krishna; Seshacharyulu, Parthasarathy; Lakshmanan, Imayavaramban et al. (2018) Cigarette Smoke Induces Stem Cell Features of Pancreatic Cancer Cells via PAF1. Gastroenterology 155:892-908.e6 |
| Nimmakayala, Rama Krishna; Batra, Surinder K; Ponnusamy, Moorthy P (2018) Unraveling the journey of cancer stem cells from origin to metastasis. Biochim Biophys Acta Rev Cancer 1871:50-63 |
| Aithal, Abhijit; Rauth, Sanchita; Kshirsagar, Prakash et al. (2018) MUC16 as a novel target for cancer therapy. Expert Opin Ther Targets 22:675-686 |
| Carmicheal, Joseph; Kaur, Sukhwinder; Batra, Surinder K et al. (2018) Hunting for transcription factors: STAT3 decoy in non-small cell lung cancer. Transl Lung Cancer Res 7:S254-S257 |
| Barkeer, Srikanth; Chugh, Seema; Batra, Surinder K et al. (2018) Glycosylation of Cancer Stem Cells: Function in Stemness, Tumorigenesis, and Metastasis. Neoplasia 20:813-825 |
| Aithal, Abhijit; Junker, Wade M; Kshirsagar, Prakash et al. (2018) Development and characterization of carboxy-terminus specific monoclonal antibodies for understanding MUC16 cleavage in human ovarian cancer. PLoS One 13:e0193907 |
| Chao, David T; Shah, Nilesh H; Zeh 3rd, Herbert J et al. (2018) Overweight or Obese Individuals at Eighteen Years of Age Develop Pancreatic Adenocarcinoma at a Significantly Earlier Age. Gastroenterol Res Pract 2018:2380596 |
| Barkeer, Srikanth; Chugh, Seema; Karmakar, Saswati et al. (2018) Novel role of O-glycosyltransferases GALNT3 and B3GNT3 in the self-renewal of pancreatic cancer stem cells. BMC Cancer 18:1157 |
| Hall, Bradley R; Cannon, Andrew; Atri, Pranita et al. (2018) Advanced pancreatic cancer: a meta-analysis of clinical trials over thirty years. Oncotarget 9:19396-19405 |
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